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Journal Pre-proof The requirement for cobalt in vitamin B12: A paradigm for protein metalation Deenah Osman, Anastasia Cooke, Tessa R. Young, Evelyne Deery, Nigel J. Robinson, Martin J. Warren PII: S0167-4889(20)30254-8 DOI: https://doi.org/10.1016/j.bbamcr.2020.118896 Reference: BBAMCR 118896 To appear in: BBA - Molecular Cell Research Received date: 8 July 2020 Revised date: 13 October 2020 Accepted date: 14 October 2020 Please cite this article as: D. Osman, A. Cooke, T.R. Young, et al., The requirement for cobalt in vitamin B12: A paradigm for protein metalation, BBA - Molecular Cell Research (2020), https://doi.org/10.1016/j.bbamcr.2020.118896 This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier. Journal Pre-proof The requirement for cobalt in vitamin B12: A paradigm for protein metalation Deenah Osmana, b, Anastasia Cookec, Tessa R. Younga, b, Evelyne Deeryc, Nigel J. Robinsona,b, Martin J. Warrenc, d, e, aDepartment of Biosciences, Durham University, Durham, DH1 3LE, UK. bDepartment of Chemistry, Durham University, Durham, DH1 3LE, UK. cSchool of Biosciences, University of Kent, Canterbury, Kent, CT2 7NJ, UK dQuadram Institute Bioscience, Norwich Research Park, Norwich, NR4 7UQ, UK eBiomedical Research Centre, University of East Anglia, Norwich, NR4 7TJ, UK Corresponding authors: Martin J. Warren and Nigel J. Robinson Email addresses: [email protected]; [email protected] [email protected] [email protected] [email protected] [email protected] Highlights The corrin-cobalt couple is ideal for forming metal-carbon bonds A fraction of bacteriaJournal make vitamin B12 andPre-proof supply other organisms including humans The biogenesis of cobalamin: Cobalt chelatases and chaperones A thermodynamic framework for metalation has been established The partitioning of cobalt into cobalamin exemplifies how cells assist metalation Journal Pre-proof Abstract Vitamin B12, cobalamin, is a cobalt-containing ring-contracted modified tetrapyrrole that represents one of the most complex small molecules made by nature. In prokaryotes it is utilised as a cofactor, coenzyme, light sensor and gene regulator yet has a restricted role in assisting only two enzymes within specific eukaryotes including mammals. This deployment disparity is reflected in another unique attribute of vitamin B12 in that its biosynthesis is limited to only certain prokaryotes, with synthesisers pivotal in establishing mutualistic microbial communities. The core component of cobalamin is the corrin macrocycle that acts as the main ligand for the cobalt. Within this review we investigate why cobalt is paired specifically with the corrin ring, how cobalt is inserted during the biosynthetic process, how cobalt is made available within the cell and explore the cellular control of cobalt and cobalamin levels. The partitioning of cobalt for cobalamin biosynthesis exemplifies how cells assist metalation. Keywords: cobalamin, cobamide, metals, chelation, homeostasis, sensors Abbreviations: CoA, co-enzyme A; GDP, guanosine diphosphate; TCA, tricarboxylic acid; GC-MS, gas chromatography–mass spectrometry; ROS, reactive oxygen species; ABC, ATP-binding cassette NiCoT, nickel/cobalt transporter; OM, outer membrane; ECF, Electron-coupled factor; SBP, substrate-binding protein; ATP, Adenosine triphosphate; MFS, major facilitator superfamily; RND, resistance nodulation division; AdoCbl, adenosylcobalamin, AqCbl, aquacobalamin; MeCbl, methylcobalamin; RBS, ribosome binding site; GTP, guanosine triphosphate; MCM, methylmalonyl-CoA mutase. Journal Pre-proof Journal Pre-proof 1 Vitamin B12 - its structure and biological roles Vitamin B12 boasts a complex façade yet mediates an abundance of intricate chemistries that ultimately derive from the properties of a central cobalt ion. This essential dietary component first came to prominence a century ago when it was identified as the anti-pernicious anaemia factor that is present in raw liver [1, 2]. The isolation of the nutrient from liver extracts was enhanced by the development of a microbial bioassay [3], using a bacterial vitamin B12 auxotroph, and culminated in the generation of purified bright red crystals [4, 5], that were shown to contain cobalt [6, 7], and which famously made their way into the hands of Dorothy Hodgkin for X-ray diffraction studies [8, 9]. Through her pioneering work she was able to deduce the structure of vitamin B12 to reveal it as the most complex structure known at that time. It is an inauspicious coincidence that the name cobalt originates from German miners who when extracting the metal for its ability to colour glass believed their ores were contaminated by a pernicious goblin, or kobold, since when heated they emitted poisonous arsenic and sulphur containing gases – and that the main human cobalt deficiency in humans is related to vitamin B12 which is also associated with a pernicious ailment. The structure of vitamin B12 can be considered in three parts (Fig. 1). Firstly, there is a modified tetrapyrrole that ligands a central cobalt ion. This tetrapyrrole-derived ring is unusual in that it has undergone a ring-contraction process meaning that one of the bridging (meso) carbon atoms that are used to connect the four pyrrole rings has been eliminated, thereby generating a macrocycle that is both contracted and lop-sided in comparison to the tetrapyrrole-frameworks that are associated with heme and chlorophylls [10]. This contracted ring structure is called a corrin. Secondly, the molecule contains a nucleotide loop that houses an unusual base, which in vitamin B12 is called dimethylbenzimidazole. The nucleotide loop is attached to one of the propionate side chains of the corrin ring through an aminopropanol linker, extending underneath the plane of the corrin ring such that the dimethylbenzimidazole base is able to act as a lower ligand for the cobalt. Finally, the third component of vitamin is the upper ligand to the cobalt ion, which in vitamin B12 is cyanide. The corrin ring and the lower nucleotide loop with its dimethylbenzimidazole base represents a molecule that is called cobalamin. Technically, vitamin B12 is therefore cyanocobalamin but vitamin B12 is quite often used loosely to refer to cobalamin. The cyano group in vitamin B12 is a consequence of the way the molecule is isolated, where cyanide is added to help its extraction and purification [11]. Some bacteria make alternative forms of cobalamin that differ in the nature of the lower nucleotide loop (Fig. 1). Here, the differences largely relate to the base that is incorporated into the loop so, for instance, some bacteria incorporate adenine rather than dimethylbenzimidazole to give rise to a cobalamin analogue that is referred to as pseudocobalamin [12]. However, across different bacterial species around 15 different variants of cobalamin are made and these are collectively referred to as cobamides or corrinoids [13, 14]. Cobalamin therefore is just one member of a broader cobamide family that all contain the same corrin ring with a liganded cobalt ion. It is the relationship between the cobalt ion and the corrin ring that is important with respect to its biological function [15, 16]. Journal Pre-proof The main active biological forms of cobalamin are where the upper ligand is either a methyl or an adenosyl group, which are present in methylcobalamin and adenosylcobalamin, respectively [17, 18]. Methylcobalamin acts as a cofactor in a number of methyl transferase reactions, including in methionine synthase. Adenosylcobalamin acts as a coenzyme in rearrangement/isomerase reactions such as with methylmalonyl CoA mutase. These two enzymes catalyse probably the two best-known B12 -dependent reactions which also represent the only two known B12 -dependent processes in mammals. However, in prokaryotes there are a range of other cobamide-dependent enzymes including the diol dehydratases, ethanolamine ammonia lyase, ribonucleotide reductase, reductive dehalogenases and a host of radical SAM enzymes [13, 19]. Adenosylcobalamin has also been shown to act as a light sensor in the CarH transcription factor [20]. Finally, cobamides can also directly influence levels of transcription and translation through interacting with riboswitches, where binding of specific cobamide forms to regulatory regions within the mRNA controls the production of encoded proteins (section 5.3.1) [21, 22]. Most cobamide riboswitches regulate genes associated with cobalt transport and cobalamin metabolism. Journal Pre-proof 1.1 Chemistry of cobalt and the corrin ring One of the long-standing questions concerning cobamides relates to why nature has selected the combination of cobalt and the corrin ring as a metalloprosthetic group partnership. What is the advantage of a corrin ring over the versatile porphyrin macrocycle of heme, and what is it about cobalt that so suits it for B12-dependent processes? This is particularly relevant given that (i) the availability of cobalt as a trace element varies